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WO2001085926A2 - Sequences nucleotidiques associees a l'augmentation ou a la reduction du taux d'ovulation mammalien - Google Patents

Sequences nucleotidiques associees a l'augmentation ou a la reduction du taux d'ovulation mammalien Download PDF

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Publication number
WO2001085926A2
WO2001085926A2 PCT/NZ2001/000073 NZ0100073W WO0185926A2 WO 2001085926 A2 WO2001085926 A2 WO 2001085926A2 NZ 0100073 W NZ0100073 W NZ 0100073W WO 0185926 A2 WO0185926 A2 WO 0185926A2
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nucleic acid
gdf
polypeptide
sequence
acid molecule
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PCT/NZ2001/000073
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WO2001085926A3 (fr
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George Henry Davis
Susan May Galloway
Kenneth Pattrick Mcnatty
Olli Visa-Pekka Ritvos
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Agresearch Limited
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Priority to MXPA02010868A priority Critical patent/MXPA02010868A/es
Priority to AU2001260821A priority patent/AU2001260821B2/en
Priority to JP2001582515A priority patent/JP2003532414A/ja
Priority to BR0110616-3A priority patent/BR0110616A/pt
Priority to CA002408051A priority patent/CA2408051A1/fr
Priority to AU6082101A priority patent/AU6082101A/xx
Priority to EP01934660A priority patent/EP1292674B1/fr
Priority to DE60134852T priority patent/DE60134852D1/de
Priority to US10/275,503 priority patent/US20040092007A1/en
Publication of WO2001085926A2 publication Critical patent/WO2001085926A2/fr
Publication of WO2001085926A3 publication Critical patent/WO2001085926A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/495—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Inheritance of the Inverdale gene on the X-chromosome provides a convenient means of producing prolific single copy Inverdale carrier ewes, because all daughters of an Inverdale carrier ram will inherit the gene.
  • the breeder of the rams uses a genetic marker test to identify carrier rams for sale, and commercial breeders purchase these rams to generate prolific ewes, which are subsequently mated to a terminal sire to produce progeny for slaughter.
  • Commercial use of the Inverdale gene has been shown to be highly beneficial in an existing terminal sire mating system, with an added value over a normal ram of $1760 per Inverdale ram purchased (Amer et al, 1998). Production of elite rams carrying the gene requires the ability to distinguish between non-carriers (++ females or +Y males) and single copy carriers (1+ females or IY males).
  • GDF-9 growth differentiation factor 9
  • TGF- ⁇ transforming growth factor beta
  • Fscl fibrous sheath component
  • Akap4 A kinase anchor protein 4
  • MMD Manton Genome Database
  • GDF-9B GDF-9B mRNA is expressed in oocytes of primary but not primordial follicles, and that expression of this mRNA within the ovary is exclusive to oocytes (Galloway et al 2000.
  • the GDF-9B coding region is contained within two exons separated by an intron of 4.2 kb (human) and 3.5 kb (mouse) (Dube et al, 1998).
  • the full-length 1176 bp coding sequence produces a 392 amino acid prepropeptide, the first 17 amino acids of which correspond to a secretory signal.
  • the full-length prepropeptide in human and mouse includes the processing site for proteolytic cleavage to release a 125 amino acid mature active C- terminal peptide and an N-terminal propeptide product (Laitinen et al, 1998, Dube et al, 1998).
  • the intron sequence lies within the propeptide domain, so that the entire mature coding region is found within exon 2.
  • the present invention is broadly directed to the mutated sequence and its corresponding encoded protein.
  • the present invention provides an isolated mutated GDF-9B nucleic acid molecule, comprising a nucleotide sequence selected from the group consisting of:
  • the present invention further provides a method of identifying a mammal which carries a mutated GDF-9B nucleic acid molecule, said method comprising the steps of:
  • Step (vi) determining whether the GDF-9B sequence DNA obtained in Step (ii) carries a mutation associated with sterility, or with increased or decreased ovulation.
  • amplication step (v) may be performed by any convenient method, such as the polymerase chain reaction, or ligase chain reaction.
  • the mammal may be male or female, and may be a human, or a domestic, companion, zoo or feral mammal.
  • the mammal is selected from humans, sheep, cattle, goats, deer, horses, camelids, possums, pigs, mice, rats, weasels, rabbits, hares, ferrets, cats and dogs.
  • the invention provides an isolated polypeptide having an amino acid sequence comprising SEQ ID NO: 10, or a functional variant or fragment thereof.
  • the invention provides an isolated nucleic acid molecule having a nucleotide sequence comprising SEQ ID NO: 9, or a functional fragment or variant thereof.
  • the invention provides a composition comprising an effective amount of a mutated GDF-9B polypeptide or a functional fragment or variant thereof, together with a pharmaceutically or veterinarily acceptable carrier or diluent.
  • the invention provides a composition comprising an effective amount of an agent selected from the group consisting of:
  • the invention provides a construct or vector comprising a nucleic acid molecule substantially as described above.
  • the present invention also provides a host cell transformed with a vector or construct comprising a nucleic acid molecule of the invention.
  • the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 12 or SEQ ID NO: 14, or a functionally active fragment or variant thereof.
  • the invention also provides an isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13 and SEQ ID NO: 15.
  • nucleic acid molecule comprising nucleic acid sequence as set forth in SEQ ID NO: 16.
  • Figure 1 shows a genetic linkage map of the ovine X-chromosome. Genetic distances are in Kosamabi centiMorgans (cM). The Inverdale gene maps into the region indicated by a hatched bar.
  • Figure 2a shows the nucleotide sequence of exon 2 of GDF-9B in Inverdale sheep.
  • the position of the Inverdale T to A nucleotide substitution (92 nucleotides beyond the processing site) is marked in bold.
  • the triplet codon affected by this substitution is underlined.
  • the processing site for proteolytic cleavage of propeptide from the mature fragment and the TGA stop codon are boxed .
  • the mature peptide coding sequence is between the two boxes.
  • Figure 2b shows the nucleotide sequence of exon 2 of GDF-9B in Hanna sheep.
  • the position of the Hanna C to T nucleotide substitution (67 nucleotides beyond the processing site) is marked in bold.
  • the triplet codon affected by this substitution is underlined.
  • the processing site for proteolytic cleavage of propeptide from mature fragment and the TGA stop codon are boxed.
  • the mature peptide coding sequence is between the two boxes.
  • Figure 2f shows the nucleotide sequence of bp 448-462 of Figure 2b.
  • Figure 4 shows a comparison of predicted amino acid sequence of sheep GDF-9B with human and mouse. Numbers in brackets above the line indicate amino acid positions of the mature peptide. The open triangle shows the position of the Leu polymorphism, and the black triangle indicates the position of the single intron. The RRAR putative processing site and the conserved cysteins are shaded grey. Positions of the FecX 1 and FecX H mutations at amino acids 23 and 31 are in bold.
  • Figure 8 shows the results of a SNP variant detection-assay of sheep carrying Inverdale FecX 1 mutation, and non-carriers, using Xba ⁇ digestion of a forced PCR frag) non- carrier, an( 1+) heterozygote and an(H) homoxygote carrier are shown beside heterozygote females (samples Al, A2), carrier rams (samples A5, A10) and non-carrier rams (samples A3, A4, A6, A7, A8, Al l, A12 and A13).
  • isolated means substantially separated or purified away from contaminating sequences in the cell or organism in which the nucleic acid naturally occurs, and includes nucleic acids purified by standard purification techniques as well as nucleic acids prepared by recombinant technology, including PCR technology, and nucleic acids which have been synthesised.
  • the nucleic acid molecule is isolated from the genomic DNA of sheep expressing the Inverdale or Hanna phenotype.
  • modulation of ovulation means increasing or decreasing the rate of ovulation compared to the rate observed in an untreated mammal.
  • Probes or primers can be free in solution or covalently or noncovalently attached to a solid support by standard means.
  • polypeptide may be produced by expression of a suitable vector comprising the nucleic acid molecule of the invention or a functional variant or fragment thereof, in a suitable host cell as would be understood by a person skilled in the art.
  • the cloning vector may be selected according to the host or host cell to be used.
  • Useful vectors will generally have the following characteristics:
  • (c) desirably, carry genes for a readily selectable marker such as antibiotic resistance.
  • the DNA molecules of the invention may be expressed by placing them in operable linkage with suitable control sequences in a replicable expression vector.
  • Control sequences may include origins of replication, a promoter, enhancer and transcriptional terminator sequences amongst others.
  • the selection of the control sequence to be included in the expression vector is dependent on the type of host or host cell intended to be used for expressing the DNA.
  • the construction of a vector it is also an advantage to be able to distinguish the vector incorporating the foreign DNA from unmodified vectors by a convenient and rapid assay.
  • Reporter systems useful in such assays include reporter genes, and other detectable labels which produce measurable colour changes, antibiotic resistance and the like.
  • the ⁇ -galactosidase reporter gene is used, which gene is detectable by clones exhibiting a blue phenotype on X-gal plates. This facilitates selection.
  • the ⁇ -galactosidase gene may be replaced by a polyhedrin-encoding gene; which gene is detectable by clones exhibiting a white phenotype when stained with X-gal. This blue-white color selection can serve as a useful marker for detecting recombinant vectors.
  • the vectors may be isolated from the culture using routine procedures such as freeze-thaw extraction followed by purification.
  • nucleotides .and peptides having substantial identity to the nucleotide and amino acid sequences of the invention can also be employed in preferred embodiments.
  • substantially identity means that two sequences, when optimally aligned such as by the programs GAP or BESTFIT (nucleotides and peptides) using default gap weights, or as measured by computer algorithm BLASTP (peptides) or BLAST X (nucleotides), share at least 60%, preferably 75%, and most preferably 90-95% sequence identity.
  • residue positions which are not identical differ by conservative amino acid substitutions. For example, the substitution of amino acids having similar chemical properties such as charge or polarity are not likely to effect the properties of a protein. Examples include gluta'mine for asparagine or glutamic acid for aspartic acid.
  • variant includes nucleic acid molecules and polypeptides and peptides having "substantial identity" to the sequences of the invention.
  • the variant may result from modification of the native nucleotide or amino acid sequence by such modifications as insertion, substitution or deletion of one or more nucleotides or amino acids or it may be a naturally-occurring variant.
  • variant also includes homologous sequences which hybridise to the sequences of the invention under standard hybridisation conditions defined as 2 x SSC at 65°C, or preferably under stringent hybridisation conditions defined as 6 x SCC at 55°C, provided that the variant is capable modulating the ovulation rate of a female mammal.
  • the invention provides the use of the mutated GDF-9B polypeptide, which has the amino acid sequence set out in figure 3a or 3b, or a variant or fragment thereof having substantial activity thereto, in a method of modulating the ovulation rate of a mammal.
  • the method may comprise administering to said mammal an effective amount of mutated or wildtype GDF-9B or antibody or antigen thereto, or a variant thereof.
  • the modulation of the ovulation rate comprises inducing sterility in the female mammal by the administration of a ligand for, or antigen of, mutated GDF-9B to reduce the level of endogenous mutated GDF-9B.
  • an additional aspect of the present invention provides a ligand which binds to a polypeptide of the invention.
  • the ligand is an antibody.
  • antibody encompasses fragments or analogues of antibodies which retain the ability to bind to a polypeptide of the invention, including but not limited to Fv, F(ab) 2 fragments, ScFv molecules and the like.
  • the antibody may be polyclonal or monoclonal, but is preferably monoclonal, i some embodiments the ligand may be a phage display molecule.
  • kits for identifying male and female mammals which carry a single (heterozygous) copy and/or females carrying two (homozygous) copies of a mutated GDF-9B nucleic acid molecule of the invention, comprising:
  • buffer salt solution for the amplification such as PCR amplification
  • thermostable DNA polymerase enzyme • control DNA from the species being tested;
  • an appropriate detection system which could comprise one of the primers in each pair being labelled fluorescently or otherwise, a labelled probe for detection of the product;
  • the invention also provides a kit for detecting circulating mutated GDF-9B protein in a mammal.
  • a kit may comprise a standard ELIS A or enzyme immunoassay format kit familiar to those skilled in the art; for example the kit may contain specific antibody directed to the mutated GDF-9B protein, and standard secondary antibody amplification components to enhance the signal.
  • the antibodies may be conjugated to a fluorescent or radioactive or chemiluminescent label, or the secondary antibody may be labelled. Appropriate solutions, controls, buffers, instructions and protocols may also be supplied.
  • Carrier status of ewes was determined by laparoscopy to identify infertile II ewes, or ovulation rate to distinguish 1+ carriers from ++ non-carriers.
  • Carrier status of rams was either assigned on the basis of ovulation rates of their daughters. Following the discovery of infertile ovaries in II ewes, a faster method for progeny testing of rams was employed by mating each ram to seven to ten 1+ ewes and carrying out laparoscopy of the daughters at 6 months. Any resulting infertile II offspring confirm the sire as a carrier. The aim was to produce five daughters per ram, as the probability of an IY ram having no daughters with streak ovaries in a sample of five daughters is only 0.031 (Davis et al. 1994).
  • Microsatellite (dinucleotide repeat) markers which amplified DNA from sheep were developed within the AgResearch Molecular Biology Unit as previously described (Galloway et al, 1996), or were from the cattle and sheep genetic mapping literature. New markers were mapped on to the sheep X-chromosome as previously described (Galloway et al, 1996).
  • PCR Polymerase Chain Reaction
  • the Leu deletion is not associated with either the FecX H or FecX 1 alleles, and appears breed-related.
  • the FecX H C ⁇ T substitution results in loss of a BsrSI restriction site (actg/gn) and gain of a Spel site (a/ctagt).
  • We confirmed this base substitution by demonstrating Spel cleavage of a 541 bp PCR product spanning this region into 476 and 65 bp fragments in FecX H IFecX H females and FecX H/Y males, but not in FecX 1 and wildtype animals, hi sheep carrying a copy of each allele (FecX 1 ! FecX H ) all three fragments were identified (541, 476 and 65bp).
  • BsrSI cleaved fragments occurred for FecX 1 and wildtype animals but not FecX H carriers.
  • a 154 bp PCR product from DNA of FecX 1 carriers produced from primers:
  • Xba ⁇ (t/ctaga) cleaved PCR products generated from FecX 1 / FecX 1 females and FecX m males carrying the A allele (tctaga), but not wildtype or FecX H PCR products carrying the T allele (tctagt).
  • Xbal cleaved the 154 bp PCR product to a 124 bp fragment by removing the 30 nucleotide primer #12 only in FecX 1 carriers. All restriction digests were carried out on aliquots of PCR products as specified by the manufacturers and fragments were separated in 3% FMC Metaphor agarose gels.
  • PCR fragments encoding the entire mature peptide were sequenced from Inverdale and Hanna genomic DNA. The sequenced region also included most of the propeptide in exon 2 (from 70 bases 3' to the human/mouse intron/exon boundary to 30 bases beyond the tga stop codon ). Sequence from these two sheep lines was compared with the wild- type sheep sequence for GDF-9B. Sequence data revealed two distinct single base substitutions within the mature GDF-9B peptide, one segregating within the Inverdale pedigree and one within the Hanna pedigree ( Figure 2).
  • a restriction enzyme search revealed that the Hanna base substitution produced a Spel enzyme cleavage site (a/ctagt) and removed a BsrSI (actg/gn) site around that substitution. These cleavage sites were confirmed by demonstrating that the enzyme Spel was able to cleave a 541bp PCR fragment spanning this region into 476bp and 65bp fragments in HY and HH animals, but not in IY and +Y animals. In a sheep carrying one copy of both the Inverdale and the Hanna genes (HI), both the 541bp and 476bp fragments were identified.
  • the sheep coding region is 82.9% homologous with human, 78.8% with mouse and 78.4% with rat at the nucleotide level.
  • FecX 1 In order to locate FecX 1 we generated a genetic linkage map of the sheep X-chromosome (Galloway et al, 1996), and we have mapped the FecX 1 locus between flanking markers 10 cM apart at the centre of the sheep X-chromosome (Figure 7). Linkage relationships with the Inverdale phenotype were observed in a family of 177 animals in a three- generation structure with a maximum of 96 informative female meioses. Linkage mapping indicated that FecX 1 mapped to a region containing TIMPl and MAOA (syntenic with human Xpll.2-11.4) and not the region containing PHKA1, XIST and ATP7A (human Xql3).
  • GDF-9B maps to human Xpl 1.2 and to a syntenic region of the mouse X-chromosome (Dube et al, 1998; Aaltonen et al, 1999).
  • the KLH-GDF-9B animals showed a highly significant increase in ovulation rate compared to the KLH control animals (p ⁇ 0.001) ANOVA.
  • Antibody levels were measured by an ⁇ LISA procedure after the sheep plasmas were diluted 1 :5000.
  • the ⁇ LISA method involved coating a 96-well plate with 100 ng/well of an E. coli expressed full-length GDF-9B and incubation with 100 ⁇ l of diluted sheep plasma and 100 ⁇ l of assay buffer, after appropriate blocking treatment and successive washes. After incubation with the sheep plasma and several washes, rabbit anti-sheep- HRP was added for 1 h at 37°C. The wells were then washed and developed with o- phenylenediamine plus hydrogen peroxide with development being stopped with sulphuric acid.
  • the number of preantral follicles in the GDF9B treated animals was significantly lower than that in the bovine ⁇ -lactalbumin treated mice, p ⁇ 0.005 (ANOVA). There were no significant differences between the treatment groups with respect to the number of antral follicles. Evidence that the differences in number of preantral follicles was associated with an antibody response to GDF-9B is as follows. The mean (range) antibody level in mouse serum diluted 1:50,000, following repeated immunisation was 2.18 (1.28-2.90) whereas all mice immunised with ⁇ -lactalbumin had no response (i.e. ⁇ 0.1). The antibody values, represented by the absorbance at 490 nm, were measured by an ELISA procedure.
  • Antibody levels were measured by an ELISA procedure as summarised for Table 4.
  • Sequence variants in the gene for GDF-9B can be determined by a variety of methods, well known to researchers skilled in the art, which are specifically designed to identify differences between alleles of the gene, hi particular these methods can be used to identify the Inverdale (FecX 1 ) and Hanna (FecX H ) single nucleotide polymorphisms (SNPs), namely the C- ⁇ T transition in FecX H carriers and the T ⁇ -A transition occurs in FecX 1 carriers, but such methods can also be applied to other alleles of this gene which may be present in other mammals. Samples can be obtained either from DNA or directly from punches of whole blood spotted directly onto FT A® paper or from hair or wool follicles.
  • One such method involves the use of restriction enzymes to cleave the DNA specifically for one allele and not the other, or to cleave t a PCR fragment containing a primer which has been designed to contain a cleavage site in combination with one allele or the other.
  • a 154 bp PCR product from DNA of FecX 1 carriers (produced from primers:
  • the Taqman allelic discrimination employs a probe technology that exploits the 5 '-3' nuclease activity of AmpliTaq Gold® DNA polymerase to allow direct detection of the PCR product by the release of a fluorescent reporter as a result of PCR. Two probes are used in the allelic discrimination assay, one probe for each allele, with each probe containing a different reporter dye.
  • the SnaPshot system is based on the dideoxy single nucleotide (fluoroescently labelled) extension of an unlabelled oligonucleotide primer for the detection of single nucleotide polymorphisms (SNPs).
  • SNP detection method employs mass spectrometry whereby the region around the SNP or mutation is amplified by PCR and an oligonucleotide primer is extended through the SNP or mutation in the presence of dideoxynucleotides. SNP variants are detected on the basis of mass difference.

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Abstract

La présente invention concerne des séquences nucléotidiques associées à l'augmentation ou à la réduction du taux d'ovulation mammalien. L'invention concerne en particulier les nouvelles mutations d'un gène associé à l'augmentation du taux d'ovulation chez les mammifères femelles hétérozygotes. Ces mutations induisent une stérilité chez les mammifères femelles homozygotes. La connaissance de la séquence génique mutée peut s'appliquer à un essai servant à identifier des mammifères femelles et mâles hétérozygotes ou homozygotes porteurs du gène muté. Cette connaissance de la fonction biologique du gène et ses mutations peut également être utilisée pour augmenter ou réduire le taux d'ovulation des mammifères femelles, ou pour induire la stérilité ou une fertilité réduite chez les mammifères femelles.
PCT/NZ2001/000073 2000-05-05 2001-05-04 Sequences nucleotidiques associees a l'augmentation ou a la reduction du taux d'ovulation mammalien WO2001085926A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
MXPA02010868A MXPA02010868A (es) 2000-05-05 2001-05-04 Secuencias de nucleotidos involucrados en el incremento o disminucion en la ovulacion mamifera.
AU2001260821A AU2001260821B2 (en) 2000-05-05 2001-05-04 Nucleotide sequences involved in increasing or decreasing mammalian ovulation rate
JP2001582515A JP2003532414A (ja) 2000-05-05 2001-05-04 哺乳類の排卵率の増加または減少に関連するヌクレオチド配列
BR0110616-3A BR0110616A (pt) 2000-05-05 2001-05-04 Sequências de nucleotìdeos envolvidas no aumento ou diminuição da taxa de ovulação em mamìferos
CA002408051A CA2408051A1 (fr) 2000-05-05 2001-05-04 Sequences nucleotidiques associees a l'augmentation ou a la reduction du taux d'ovulation mammalien
AU6082101A AU6082101A (en) 2000-05-05 2001-05-04 Nucleotide sequences involved in increasing or decreasing mammalian ovulation rate
EP01934660A EP1292674B1 (fr) 2000-05-05 2001-05-04 Sequences nucleotidiques associees a l'augmentation ou a la reduction du taux d'ovulation mammalien
DE60134852T DE60134852D1 (de) 2000-05-05 2001-05-04 Nukleotidsequenzen, die an erhöhung oder verringerung von der ovulationsgeschwindigkeit in säugertieren beteiligt sind
US10/275,503 US20040092007A1 (en) 2000-05-05 2001-05-04 Nucleotide sequences involed in increasing or decreasing mammalian ovulation rate

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NZ500844A NZ500844A (en) 2000-05-05 2000-05-05 Nucleotide sequences (mutated GDF-9B polypeptides) involved in increasing and decreasing mammalian ovulation rate
NZ500844 2000-05-05

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096393A3 (fr) * 2000-06-15 2002-08-08 Agres Ltd Sequences de nucleotides et d'acides amines de facteurs derives d'ovocytes permettant de modifier la croissance folliculaire ovarienne in vivoet in vitro
WO2003102199A1 (fr) * 2002-05-30 2003-12-11 Ovita Limited Nouvelles sequences gdf-9 et gdf-9b (bmp-15) destinees a modifier la fonction ovarienne et la vitesse d'ovulation chez des mammiferes
WO2006059914A1 (fr) * 2004-12-02 2006-06-08 Agresearch Limited Modulation de l'ovulation
EP1947195A4 (fr) * 2005-09-13 2009-11-04 Neocodex S L Methode de detection in vitro de la predisposition a developper des alterations de la fonction ovarienne
ES2338960A1 (es) * 2007-11-23 2010-05-13 Carnes Oviaragon S.C.L. Procedimiento de mejora de la productividad en ganado ovino.
CN106614366A (zh) * 2016-12-29 2017-05-10 李振民 一种无抗生猪养殖方法
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WO2001096393A3 (fr) * 2000-06-15 2002-08-08 Agres Ltd Sequences de nucleotides et d'acides amines de facteurs derives d'ovocytes permettant de modifier la croissance folliculaire ovarienne in vivoet in vitro
WO2003102199A1 (fr) * 2002-05-30 2003-12-11 Ovita Limited Nouvelles sequences gdf-9 et gdf-9b (bmp-15) destinees a modifier la fonction ovarienne et la vitesse d'ovulation chez des mammiferes
AU2003235525B2 (en) * 2002-05-30 2008-09-11 Agresearch Limited New GDF-9 and GDF-9B (BMP-15) sequences for altering mammalian ovarian function and ovulation rate
WO2006059914A1 (fr) * 2004-12-02 2006-06-08 Agresearch Limited Modulation de l'ovulation
EP1947195A4 (fr) * 2005-09-13 2009-11-04 Neocodex S L Methode de detection in vitro de la predisposition a developper des alterations de la fonction ovarienne
ES2338960A1 (es) * 2007-11-23 2010-05-13 Carnes Oviaragon S.C.L. Procedimiento de mejora de la productividad en ganado ovino.
ES2338960B1 (es) * 2007-11-23 2011-04-19 Carnes Oviaragon S.C.L. Procedimiento de mejora de la productividad en ganado ovino.
CN106614366A (zh) * 2016-12-29 2017-05-10 李振民 一种无抗生猪养殖方法
CN108753835A (zh) * 2018-05-30 2018-11-06 中山大学 一种利用CRISPR/Cas9编辑猪BMP15基因的方法

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EP1292674A2 (fr) 2003-03-19
AR028411A1 (es) 2003-05-07
NZ500844A (en) 2003-06-30
AU2001260821B2 (en) 2006-04-13
ATE401403T1 (de) 2008-08-15
WO2001085926A3 (fr) 2002-08-08
ZA200208963B (en) 2004-07-26
DE60134852D1 (de) 2008-08-28
CA2408051A1 (fr) 2001-11-15
CN1436237A (zh) 2003-08-13
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